Catalytic inhibitor of Protein Phosphatase 5 activates the extrinsic apoptotic pathway by disrupting complex II in kidney cancer.

Serine/threonine protein phosphatase-5 (PP5) is involved in tumor progression and survival, making it an attractive therapeutic target. Specific inhibition of protein phosphatases has remained challenging because of their conserved catalytic sites. PP5 contains its regulatory domains within a single polypeptide chain, making it a more desirable target. Here we used an in silico approach to screen and develop a selective inhibitor of PP5. Compound P053 is a competitive inhibitor of PP5 that binds to its catalytic domain and causes apoptosis in renal cancer. We further demonstrated that PP5 interacts with FADD, RIPK1, and caspase 8, components of the extrinsic apoptotic pathway complex II. Specifically, PP5 dephosphorylates and inactivates the death effector protein FADD, preserving complex II integrity and regulating extrinsic apoptosis. Our data suggests that PP5 promotes renal cancer survival by suppressing the extrinsic apoptotic pathway. Pharmacologic inhibition of PP5 activates this pathway, presenting a viable therapeutic strategy for renal cancer. [Display omitted] • PP5 mediates dephosphorylation and inactivation of the death effector protein FADD • PP5 maintains the integrity of complex II and regulates the extrinsic apoptosis • Development of competitive inhibitors of serine/threonine protein phosphatase-5 • Pharmacologic inhibition of PP5 activates the extrinsic apoptosis in renal cancer Ahanin et al. show that protein phosphatase-5 (PP5) down-regulates the extrinsic apoptotic pathway by dephosphorylating the death effector protein FADD, therefore preserving complex II integrity in cancer. A competitive inhibitor of PP5 designed in this study causes disruption of complex II and activation of extrinsic apoptotic pathway in renal cancer. [ABSTRACT FROM AUTHOR]